Hippocampal-anterior thalamic pathways for memory: uncovering a network of direct and indirect actions

Abstract

This review charts recent advances from a variety of disciplines that create a new perspective on why the multiple hippocampal-anterior thalamic interconnections are together vital for human episodic memory and rodent event memory. Evidence has emerged for the existence of a series of parallel temporal-diencephalic pathways that function in a reciprocal manner, both directly and indirectly, between the hippocampal formation and the anterior thalamic nuclei. These extended pathways also involve the mammillary bodies, the retrosplenial cortex and parts of the prefrontal cortex. Recent neuropsychological findings reveal the disproportionate importance of these hippocampal-anterior thalamic systems for recollective rather than familiarity-based recognition, while anatomical studies highlight the precise manner in which information streams are kept separate but can also converge at key points within these pathways. These latter findings are developed further by electrophysiological stimulation studies showing how the properties of the direct hippocampal-anterior thalamic projections are often opposed by the indirect hippocampal projections via the mammillary bodies to the thalamus. Just as these hippocampal-anterior thalamic interactions reflect an interdependent system, so it is also the case that pathology in one of the component sites within this system can induce dysfunctional changes to distal sites both directly and indirectly across the system. Such distal effects challenge more traditional views of neuropathology as they reveal how extensive covert pathology might accompany localised overt pathology, and so impair memory.

Fig. 1

Diagrammatic representation of the location of the fornix and its divisions. The dashed arrows show fornical connections that are solely efferent from the hippocampal formation, the narrow solid arrows show fornical connections that are solely afferent to the hippocampal formation, and the wide solid arrows show reciprocal connections within the fornix. AC, anterior commissure; ATN, anterior thalamic nuclei; HYPOTH, hypothalamus; LC, locus coeruleus; LD, thalamic nucleus lateralis dorsalis; MB, mammillary bodies; MTT, mammillothalamic tract; RE, nucleus reuniens; SUM, supramammillary nucleus.

Fig. 2

Patients with atrophied mammillary bodies (SMB) show a selective loss of recollective-based recognition, based on the Remember/Know procedure. Derived probability estimates of ‘Recollection’ and ‘Familiarity’ come from a Small Mammillary Body (SMB, n = 9) and a Large Mammillary Body (LMB, n = 9) group, both drawn from a cohort of post-surgery colloid cyst patients (Vann et al., 2009a,;). While the two groups differ markedly on ‘Recollection’ (P < 0.005), they do not differ on ‘Familiarity’. In a yes/no recognition test participants were asked to make a subjective judgment about their ‘yes’ responses, giving a decision as to whether they were ‘recollective’ in nature (accompanied by other information associated with their initial exposure to the target) or ‘familiar’ in nature (a sense of familiarity devoid of other information). Data presented in histograms are means ± SEM. ‘Familiarity’ is the probability of a familiar response given the item was not recollected (F/(1−R)). Recollection is the probability an old item had a remember response minus the probability that new item had a remember response. To address false alarm rates, familiarity was first estimated for ‘old’ items and for ‘new’ items, and then familiarity for new items was subtracted from familiarity for old items.

Fig. 3

Example stimuli depicting different classes of configural discrimination. Left: biconditional discrimination, where all four elements A, B, X, Y, are found equally in the rewarded (+) and nonrewarded (−) compound stimuli. Middle: depiction of the structural discrimination, A to the left of X vs. X to the left of A. Note, this task can be solved nonstructurally if the subject always attends to just the extreme left (or right) element of the compound stimulus as now it can be solved elementally using A− and X+. Right: formal set of concurrent structural discriminations that are used to ensure that subjects cannot solve the task merely by attending to just one side of each compound stimulus.

Fig. 5

Diagram of interlinked connections in the rat brain showing how the hippocampal formation is associated with three distinct sets of parallel anterior thalamic connections. Connections conveyed in the fornix are shown as dashed lines. Double-headed arrows depict reciprocal connections. The connectivity of the interoanteromedial nucleus is taken from Hopkins (2005). DtG, dorsal tegmental nucleus of Gudden; MTT, mammillothalamic tract; VtGa, ventral tegmental nucleus of Gudden, pars anterior; VtGp, ventral tegmental nucleus of Gudden, pars posterior.

Fig. 4

Contrasting distribution of dorsal subicular cells projecting to the anterior thalamic nuclei (ATN) and mammillary bodies (MB). Coronal colour section through the dorsal subiculum (right hemisphere) showing the separate populations of subicular cells projecting to the anterior thalamic nuclei (red cells, fast-blue injection) and the mammillary bodies (green cells, cholera toxin-488 injection). The dashed line shows the division, with those cells closest to the alveus (upper) projecting to the thalamus (ATN). White scale bar, 250 μm.